The increased emergence of antibiotic resistance has been linked to the overuse of antibiotics, particularly in hospitals. Antimicrobial stewardship programs are widely acknowledged as essential to improve appropriate antibiotic use, decrease antimicrobial resistance, and reduce cost. However, few data exist describing the efficacy of such programs in pediatric populations, particularly in the neonatal intensive care unit (NICU). The long-term objectives of this study are to reduce antimicrobial resistance by implementing innovative interdisciplinary interventions aimed to improve antibiotic prescribing practices in the NICU and thereby define the optimal interventions for this population. The Specific Aims are to: 1) measure the impact of three interdisciplinary intervention bundles on inappropriate antimicrobial use as categorized by the CDC 12 Step Campaign Program to Prevent Antimicrobial Resistance;2) determine the impact of these . intervention bundles on resistance density, i.e., changes in the rate of infant infections and colonization with multidrug-resistant organisms (MDROs) and changes in the proportion of MDROs carried on NICU staff hands;and 3) determine the cost effectiveness of the intervention bundles in preventing bloodstream infections caused by MDROs. The Study Design is a quasi-experimental prospective clinical trial whereby 4 study NICUs in the United States (total beds - 214, annual discharges - 3649) will berandomized to successive bundles of interventions versus usual care to determine which combinations of interventions have the greatestjmpact on appropriate antibiotic use, antimicrobial resistance, and cost. The interventions have beendeveloped using the PRECEDE-PROCEEDhealth promotion planning model which suggests that programsto change health behavior should include predisposing, enabling, and reinforcing factors. Thus, the Education intervention in this study addresses the predisposing knowledge and beliefs of staff regarding antimicrobial resistance and helps set goals for improving prescribing practices. The Clinical Decision Support- Computerized Provider Order Entry intervention provides computer prompts in the electronic health record to enable better decisions about stopping, changing, or continuing antibiotic treatment. The Audit and Prescriber Feedback intervention reinforces desired prescribing practices as providers can monitor the success of their prescribing decisions on health outcomes and receive praise and encouragement from the study team.